PROJECT SUMMARY Project Title: Recombinant TIL Cell Therapy for Salvage Solid Tumor Patients Organization: GigaMune Inc. PI: Matthew J Spindler, Ph.D. Expanded T cells isolated from tumor infiltrating lymphocytes (TILs) have achieved remarkable clinical efficacy for the treatment of metastatic melanoma. TILs are composed of a polyclonal mix of tumor-reactive T cell receptors (TCRs), and several pioneering groups have isolated individual therapeutic TCRs targeting public tumor-associated antigens from TILs. The anti-tumor TCRs within the TIL population are able to target the many intracellular and patient-specific neoantigen targets not previously druggable. However, ex vivo expansion of TILs is labor intensive, time consuming, and may result in cellular phenotypic changes that could reduce efficacy. Isolating TCRs from pre-expanded ?young? TIL populations would alleviate these issues and could be converted into a recombinant anti-tumor therapy. Leaders in the field have proposed that primary T cells engineered with polyclonal anti-tumor TCRs could be an ideal therapeutic approach. However, conventional T cell discovery relies on low-throughput methods and requires subsequent cloning of individual reactive TCRs. Generating a true ?recombinant TIL? therapy requires a technology that can capture millions of T cells per hour and produce polyclonal libraries of TIL TCRs with native TCRa/b pairing. Previously, we developed GigaLink?, a world-leading technology for generating recombinant TCR repertoires from primary T cell samples. We have used this technology to make expression libraries of natively paired TCRs from five clinically-validated malignant melanoma TILs. The Specific Aim of this Phase I SBIR project is to generate pre-clinical efficacy data in mouse models for a recombinant TIL T-cell therapeutic approach for the personalized treatment of cancer. We will achieve the Specific Aim by applying our GigaLink? technology to patient derived xenograft (PDX) tumor models in mice.